The present invention relates generally to the topical inhibition of the metabolic activity of cytochrome P450 and more specifically to the topical administration of cytochrome P450 inhibitors to facilitate localized inhibition of the metabolic activity of different enzymes within the cytochrome P450 family.
It will be appreciated by those skilled in the art that topical steroids are currently the drugs of choice for the treatment of moderate and severe asthma. Though topical steroids are generally well tolerated and have less side effects than systemic steroids, the possibility of side effects, including osteoporosis, impeded linear growth in children and cataract formation, is still a concern.
Corticosteroids have been used to treat asthma since 1950. These drugs do not relax smooth muscle in the airway directly. It has been suggested by studies that corticosteroids may act by up-regulating .beta.-receptors as well as by inhibiting the inflammatory response in the airways. Because of severe adverse effects when oral corticosteroids are given chronically, oral steroids are generally reserved for patients who are not maintained adequately with bronchodilators or for acute treatment in patients with worsening symptoms despite bronchodilator therapy.
The introduction of inhaled corticosteroids was, therefore, a great therapeutic advance. By introducing lipid soluble corticosteroids in aerosol form, an effective method of delivering corticosteroids to the airways with minimal systemic absorption and reduced adverse effects was established.
There have also been attempts to develop a more effective inhalation method for the treatment of asthma. One such attempt was disclosed in U.S. Pat. No. 4,089,959, issued to J. Diamond on May 16, 1978 which describes a long-acting xanthine bronchodilator. This long-acting xanthine was an attempt of an improvement over previously developed substituted xanthines and the well known theophylline (1-3-dimethylxanthine). None of the compounds used in the present invention are related to the family of substituted xanthines described in the '959 patent.
Another such attempt was made in U.S. Pat. No. 5,081,114, issued to J. Gourvest, et al on Jan. 14, 1992 which disclosed novel steroid compounds. Use of these steroids is unrelated to the present invention. These steroids are capable of inducing aromatase specific activity (cytochrome P450 aromatase) in warm-blooded animals. The use of aromatase specific activity induction is found useful in the treatment of cancer of the breast, endometrium, ovary, pancreas and etc. However, no mention is made of treatment of asthma by using this compound and no mention is made of topical inhibition of cytochrome P450 enzymes.
U.S. Pat. No. 5,215,965, issued to J. Lezdey, et al on Jun. 1, 1993, describes a treatment for inflammation by administering a corticosteroid in combination with at least one serine protease inhibitor, its salts, derivatives or analogs which bind the mediators of mast cells or T-cells. The '965 invention addresses the fact that in certain pulmonary diseases, neutrophils, mast cells, T-cells, and their mediators induced an inflammatory state resulting in a localized imbalance of elevated serine protease with an accompanying reduction in their naturally occurring inhibitors. Although this combination of compounds is via inhalatory route, it differs greatly from the combination suggested in the proposed invention.
In the article by Mary Ann Christopher, et al. entitled Clinical Relevance of the Interaction of Theophylline with Diltiazem or Nifedipine published in Chest, February, 1989: 95(2): 309-313, the authors demonstrated that although calcium channel blockers are capable of inhibiting cytochrome P-450 activity in hepatic microsomes (the pathway of theophylline metabolism), the actual metabolism of theophylline was not effected by administration of certain administered calcium channel blockers. This study, although it deals with P-450 activity and compounds which inhibit the same activity, is unrelated to the present invention.
The Effects of Imidazole Derivatives on Cytochrome P-450 From Human Hepatocytes in Primary Culture, FASEB J 1992; 6:752-58 by Manuelle Mattrice, et al., reported on in vitro tests on human hepatocytes which examined the effects of imidazole derivatives on cytochrome P-450. Ketoconazole was found to be a strong and selective inhibitor of P-450 3A (cyclosporin oxidase or CYP 3A). However, an application of that inhibition was not further discussed in the paper nor suggested.
Cytochrome P-450 is a superfamily of enzymes that metabolize a large number of drugs, xenobiotics and endogenous substances in vitro and in vivo. The cytochrome P-450 3A (CYP 3A) isoenzyme is a member of the cytochrome P-450 superfamily. It constitutes up to 60% of the total human liver microsomal cytochrome P-450 and is responsible for metabolism of a large number of drugs including nifedipine, macrofide antibiotics including erythromycin and troleandomycin, cyclosporin, FK506, teffenadine, tamoxifen, lidocaine, midazolam, triazolam, dapsone, diltiazem, lovastatin, quinidine, ethylestradiol, testosterone, and alfentanil.
Metabolism of cortisol to 6-b-hydroxycortisol has also been shown to be specifically mediated by cytochrome P450 in vitro and in vivo. In addition, CYP 3A has been shown to be involved in both bioactivation and detoxication pathways for several carcinogens in vitro. (Bibliography refs. 1 and 2)
The active form of CYP 3A has been found in other organs besides the liver including kidney epithelial cells, jejunal mucosa, and the lungs. In these organs, the amount of the cytochrome P450 protein is much lower then in the liver. In a study of human lung microsomes, presence and activity of CYP 3A has been demonstrated. (Bibliography ref. 3)
Presence of the cytochrome P-450 3A in the lung microsomes indicates that the drugs and other substances which are subject to CYP 3A (P450-3A) mediated metabolism may be partially metabolized in the lungs. This has been demonstrated for the topical steroid, beclomethasome dipropionate. It has also been shown that only about 10% of the drug released by an inhaler is available to the lungs. The remaining mount is retained in the spacer device and oral cavity. Steroids absorbed from the lungs and gastrointestinal tract are subsequently metabolized by hepatic cytochrome P450. (Bibliography ref. 4)
The ideal topical steroid for asthma therapy should have very high topical activity, and be poorly absorbed from the lungs and GI tract with the absorbed portion of the dose quickly metabolized by the liver enzymes.